1-substituted-4-aryl-2(1h)-quinazolinones and their preparation

ABSTRACT

Compounds are of the class of 1-substituted-4-aryl-2(1H)quinazolinones, e.g., 1-ethyl-4-phenyl-2(1H)-quinazolinone, which are useful as anti-inflammatory agents, antipyretics and analgesics. The compounds are prepared by any one of several processes including, inter alia, the cyclization of a 2alkylaminobenzophenone with urethane, the cyclization of a 2alkylaminobenzophenonimine with phosgene, the reaction of a 1alkali metal salt of a 4-aryl-2(1H)-quinazolinone with an alkyl halide or from a 1-unsubstituted-4-arylquinazoline which is reacted with a methyl halide to form the corresponding 1-methylquinazolinium halide which is either then directly oxidized or first reduced and then oxidized to obtain the 1-methyl-4-aryl2(1H)-quinazolinone. Novel intermediates disclosed include the 1methyl-4-aryl-quinazoliniums and compounds which are 1-methyl-4aryl-3,4-dihydroquinazolines.

United States Patent [191 in] 3,723,432

Ott 1 Mar. 27, 1973 154] l-SUBSTlTUTED-4-ARYL-2(1H)- QUINAZOLINONES ANDTHEIR PREPARATION Inventor: Hans Ott, Pfeffingen, Basel-Land,

Switzerland Assignee: Sandoz-Wander, Hanover,

Filed: Nov. 12, 1968 Appl. No.: 775,201

Inc.

Related U.S. Application Data U.S. Cl...260/251 QB, 260/251 Q, 260/2564Q,

260/556 R, 260/2565 R, 424/251 Int. Cl. ..C07d 51/48 Field of Search..260/251 Q, 256.4 Q, 256.5

References Cited UNITED STATES PATENTS 6/1969 Bell et a1. ..260/309.5

Primary Examiner-Alex Mazel Assistant Examiner-R. V. Rush Azt0rneyGeraldD. Sharkin, Richard E. Vila, Robert S. Honor, Frederick H. Weinfeldt andWalter F. Jewell [57] ABSTRACT Compounds are of the class ofl-substituted-4-aryl- 2(1H)-quinazolinones, e.g.,1-ethyl-4-phenyl2(lI-I)- quinazolinone, which are useful asanti-inflammatory agents, antipyretics and analgesics. The compounds areprepared by any one of several processes including, inter alia, thecyclization of a 2-alkylaminobenzophenone with urethane, the cyclizationof a 2-alkylaminobenzophenonimine with phosgene, the reaction of al-alkali metal salt of a 4-aryl-2(1H)- quinazolinone with an alkylhalide or from a l-unsubstituted-4-arylquinazoline which is reacted witha methyl halide to form the corresponding l-methylquinazolinium halidewhich is either then directly oxidized or first reduced and thenoxidized to obtain the l-methyl-4-aryl-2(1H)-quinazolinone. Novelintermediates disclosed include the l-methyl-4-aryl-quinazoliniums andcompounds which are l-methyl-4-ary1- 3,4-dihydroquinazolines.

70 Claims, N0 Drawings l -SUBSTITUTED-4-ARYL-2(1H)- QUINAZOLINONES ANDTHEIR PREPARATION This application is a continuation-in-part of mycopending application Ser. No. 741,804, filed July 1, 1968, which is acontinuation-in-part of application Ser. No. 707,932, filed Feb. 26,1968, which is a continuation-in-part of application Ser. No. 672,739,filed Oct. 4, 1967, which is a continuation-in-part of application Ser.No. 636,015, filed May 4, 1967, which is a continuation-in-part of mycopending application Ser. No. 575,511, filed Aug. 29, 1966, now allabandoned.

This invention relates to bicyclic compounds. In particular, theinvention pertains to 1-substituted-2(1H)- quinazolinones and methods ofpreparing the same. The invention also relates to intermediates whichare useful in the preparation of the above compounds and to processesfor preparing said intermediates.

The chemical compound which is 4-phenyl-2(1H)- quinazolinone has beenknown for some time and described in the literature, e.g., see Gabrieland Stelzney, Chem. Berichte 29, 1300 (1896) and Schofield, J. Chem.Soc. (London) 1952, 1927. No pharmacological activity has beenassociated with said 4-phenyl-2(1 H)-quinazolinone.

The quinazolinones of the present invention may be representedstructurally as follows:

wherein R represents hydrogen; halo, preferably having an atomic weightno greater than 80, i.e. fluoro, bromo and chloro; lower alkyl,preferably containing one to three carbon atoms; lower al-' koxy,preferably containing one to two carbon atoms; hydroxy; nitro; amino;cyano; acetamido; trifluoromethyl; mercapto; lower alkylthio where thealkyl is of one to two carbon atoms; lower alkylamino of one to fourcarbon atoms; or di(lower)alkylamino where each alkyl is of one to fourcarbon atoms;

n is 1 or 2, and when 2 then: A) one and the other R is, independently,halo, lower alkyl or lower alkoxy, or the other R is one of nitro,amino, N-alkylamino and dialkylamino; or B) one R is Nalkylamino ordialkylamino while the other R is nitro; v

R represents lower alkyl, preferably containing from one to five carbonatoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl andisobutyl; allyl, methallyl; or propargyl; provided R is not anunsaturated hydrocarbon substituent when R is N-alkylamino;

R represents phenyl; or substituted phenyl of the formula Y representshalo, hydroxy, lower alkyl, preferably containing from one to threecarbon atoms, e.g., methyl, ethyl, propyl and butyl, lower alkoxy,preferably containing from one to two carbon atoms, e.g., methoxy,ethoxy, propoxy and butoxy; or trifluoromethyl; and

Y represents hydrogen, halo, hydroxy, lower alkyl,

preferably containing from one to three carbon atoms, e.g., methyl,ethyl, propyl and butyl, or lower alkoxy preferably containing from oneto two carbon atoms, e.g., methoxy, ethoxy, propoxy and butoxy; or apharmaceutically acceptable acid addition salt thereof.

In the preferred method for preparing the compounds of structuralformula I, an appropriately substituted o-aminobenzophenone is cyclizedby reacting with ethyl carbamate in the presence of a suitable Lewisacid, e.g., zinc chloride. Another preferred method involves cyclizingan appropriately substituted o-aminobenzophenonimine, preferably byreaction with phosgene. Alternatively, the compounds of formula I may beprepared by reacting an alkali metal salt of an appropriatelysubstituted quinazolinone with an appropriate halide (RX). Thosecompounds of formula I wherein R is limited to methyl (and R and R" areas defined) may also be prepared by reacting an appropriatelysubstituted quinazoline with a methyl halide to form the correspondingl-methyl halide salt thereof and then either oxidizing the latter toform the desired quinazolinone or first reducing the halide salt to formthe corresponding l,2,3,4-tetrahydroquinazoline and then oxidizing thelatter to form the quinazolinone. These processes may be illustrated, asfollows:

VII I wherein R, n, R and R" are as defined above, M represents analkali metal, preferably sodium or potassium, and X represents halogen,preferably iodo.

Step I of the above-illustrated processes is conveniently carried out atelevated temperatures and in the presence of a catalytic amount of zincchloride. Preferably, the reaction is effected at a temperature of fromabout l60 C. to about 200 C. If desired, the reaction may be carried outin the presence of a suitable inert organic solvent. However, the use ofa solvent is not necessary since an excess of the carbamate can be usedfor this purpose. Depending upon the particular conditions employed thereaction time will generally vary from about 30 minutes to about 2hours.

The conversion of the l-metallo quinazolinone (III) to the desiredquinazolinone (I), as illustrated by Step 2, is conveniently carried outat room temperature (20 C.) or at elevated temperatures of up to about lC. Desirably, the reaction of the salt with the appropriate halide,preferably the iodide, is carried out in the same solvent employed toprepare the l-metallo derivative (III). The preparation of the latter isreadily carried out by treating the corresponding l-unsubstitutedquinazolinone in conventional manner, with any of the conventionalagents commonly employed for preparing alkali metal salts, e.g., sodiumhydride and the alkali metal alkoxides such as sodium methoxide, sodiumethoxide, potassium methoxide and potassium ethoxide. The formation ofthe salt, preferably the sodium or potassium salt, is convenientlycarried out in a suitable inert organic solvent, e.g.,dimethylacetamide, diethylacetamide, dimethylformamide,dimethylsulfoxide and dioxane, and at room temperature.

The reaction of the quinazoline (IV) with the methyl halide (Step 3) iscarried out at room temperature (20 C.) or elevated temperatures of upto about 45 C. employing either an excess of the halide reactant or asuitable inert organic solvent as the reaction medium. Preferably, thereaction is initially carried out at room temperature and then continuedat reflux temperature employing an excess of methyl iodide as the halidereactant. If it is desired to employ a solvent rather than an excess ofthe halide reactant, any inert organic solvent commonly employed forcarrying out reactions of this nature, e.g., chloroform and acetone, canbe employed. When the halide employed is a gas at ordinary roomtemperature, a suitable inert organic solvent is generally employed asthe reaction medium.

The conversion of the quinazolinium halide (V) to the correspondingtetrahydroquinazoline (VI), as illustrated by Step 5, can be achieved bychemical reduction employing a suitable borohydride, e.g., sodiumborohydride, as the reducing agent. The reduction is convenientlyeffected in a suitable organic solvent, e.g., a lower alkanol such asmethanol or ethanol, and mixtures of lower alkanols with methylenechloride, chloroform or water. The reaction temperature is desirably inthe range of from about room temperature (20 C.) to about 80 C.

The oxidation (Step 4) of the quinazolinium halide (V) ortetrahydroquinazoline (VI) is readily effected in the presence of anysuitable inert organic solvent, e.g., dioxane and acetone, at roomtemperature employing sodium permanganate or potassium permanganate asthe oxidizing agent.

In each of the steps discussed above, the product obtained can bereadily recovered employing conventional techniques. However, it shouldbe noted that the products obtained from Step 5 are somewhat unstableand therefore it is generally desirable to convert the same to thedesired quinazolinone (Ia), as described 5 hereinabove, as soon aspossible.

The production of compounds of formula I by Step 6 involving thereaction of an o-benzophenonimine of formula VII with phosgene may becarried out at temperatures in the range of 0 C. to 50 C., preferably 10C. to 30 C. The reaction of Step 6 is desirably carried out in an inertorganic solvent which may be any of the several convenient for thepurpose, preferably an aromatic hydrocarbon, e.g., benzene, toluene, andxylene, more preferably benzene. The mole ratio of phosgene to compoundVII is not particularly important and a substantial excess of phosgeneis employed in the preferred forms of practice to obtain more efficientreaction rates. The compounds of formula I may be obtained from thereaction mixture of Step 6 by working up in a conventional manner.Preparation of the compounds of formula I in which R represents an alkylsubstituent having a tertiary carbon atom attached to the ring nitrogenis not well-suited to the other aboveillustrated processes but suchcompounds have been found to be readily produced by cyclizing anappropriately substituted o-tert. butyl-benzophenonimine of formula VIIwith phosgene in accordance with the procedure of Step 6.

Certain of the compounds I of the invention may also be employed toproduce other compounds I of the invention. For example, those compoundsof formula I wherein R is as defined, and one or more of R, Y and Y ishydroxy or mercapto, are usually most desirably prepared from thecorresponding alkoxy and alkylthio derivatives, respectively, byhydrolyzing such derivatives under acidic conditions. The hydrolysis iscarried out in conventional manner employing the usual conditionsgenerally utilized for converting an alkoxy or alkylthio grouprespectively to a hydroxy or mercapto group, e.g., by treatment of saidderivative with aqueous hydrobromic acid or hydrobromic acid in aceticacid.

Additionally, compounds of formula I in which R is nitro may be producedby direct nitration of other compounds as illustrated herein in Example49. Also, compounds I in which R is nitro or amino may be employed inproducing other compounds of formula I such as those in which R is halo,amino, acetamido, cyano, hydroxy, mercapto, N-alkylamino anddialkylamino. The conversion of compounds I in which R is nitro or aminoto other compounds I may be carried out by one or more of severalgenerally known procedures and in most situations represents thepreferred manner of preparing compounds of formula I in which R isamino, cyano, acetamido and various compounds I in which R isN-alkylamino or dialkylamino. It is thus possible to produce compounds Iin which R is amino from corresponding compounds I in which R is nitroemploying a suitable elemental metal reducing agent such as iron, and anacidic reaction medium, as illustrated in Example 25. The compounds I inwhich R is amino may be also converted by the well-known Sandmeyerreaction to various compounds I, as illustrated by Examples 27 and 28.The Sandmeyer reaction is usually preferred in producing compounds I inwhich R is cyano, but may also be applied to other significances of Rsuch as halo, particularly bromo, hydroxy, mercapto, alkoxy oralkylthio. The compounds I in which R is amino are also useful inproducing the corresponding acetamido derivative by reaction with aceticanhydride in a suitable solvent such as pyridine, as illustrated byExample 26.

The preparation of compounds of formula I in which R is N-alkylamino ordialkylamino is preferably carried out by the above-indicated reactionsof Step 1 or Step 6 or by reacting a compound I in which R is nitro oramino according to the procedures illustrated as foll lows:

Step 7 wherein R, R" and X areas defined above, R is N- alkylamino ordialkylamino, R is hydrogen, halo, lower alkoxy or lower alkyl, and R isalkyl of one to four carbon atoms.

The preparation of compounds lb by Step 7 involving reaction of acompound Vlll with an alkyl halide is an alkylation reaction of knowntype conveniently carried out in an organic solvent at temperatures inthe range of from C. to 150 C., usually 50 C. to 100 C. The reaction isdesirably carried out in the presence of a base of which the inorganicbases, particularly an alkali metal carbonate, e.g., sodium carbonate,are preferred. In most situations the alkyl halide may be convenientlyemployed in excess as solvent for the reaction. Other well known organicsolvents may be also employed. Representative of the more suitableconventional sol vents are dioxane, benzene and toluene. The reaction ofStep 7 may be varied to produce compounds of formula IA in which thebenzene ring portion of the quinazolinone is substituted by eitherN-alkylamino or dialkylamino. In general, the shorter reaction periodsare employed when producing the N-alkylamino derivatives. The longerreaction times and higher temperatures are conditions favoring theproduction of the dialkylamino derivatives. Techniques convenientlyemployed in the alkyl halide alkylation of amines may be also employedto advantage in preparation of the compounds of invention by Step 7. Forexample, it is within the scope of Step 7 to tosylate the amino group ofthe compound Vlll prior to alkylation followed by detosylation afteralkylation in producing compounds in which R represents a N-(lower)alkylsubstituent. The product compound lb may be isolated from the reactionmixture of Step 7 by working up in a known manner.

The preparation of compounds lb by Step 8 involves reaction of acompound Vlll with a lower alkanol of two to four carbon atoms in thepresence of Raney Nickel and is a reductive alkylation of known type.The reaction is conveniently carried out in an organic solvent attemperatures in the range of from 30 C. to 150 0 C., preferably 50 C. to100 C. While any of several conventional organic solvents may beemployed, it is convenient and generally preferred to employ an excessof the lower alkanol as solvent. Examples of other more suitableconventional solvents include dioxane and ethyl acetate. The reaction ofStep 8 is especially useful in producing compounds of formula lA havingan N-alkylamino substituent of two to four carbon atoms and for thispurpose the shorter reaction periods in the range of about 30 minutes toabout 5 hours are usually satisfactory. The use of an excess of RaneyNickel has been found to assist in the preparation of the N-alkylaminoderivatives. The product compound lb may be isolated from the reactionmixture by working up in a conventional manner.

Preparation of compounds lb by Step 9 involving reaction of a compoundIX with hydrogen and a lower aldehyde in the presence of a reducingmetal catalyst is a reductive alkylation of known type. The reaction maybe conveniently carried out in an organic solvent at elevated pressuresand at temperatures in the range of 10 C. to C., typically at about roomtemperature. Pressures of from 1 to 5 atmospheres above normalatmospheric pressure are suitably employed. The solvent preferablyemployed in methanol or the alkanol corresponding in carbon atoms to thealdehyde. However, other solvents of conventional type may be used, forexample, dioxane and ethyl acetate. The reducing metal catalystdesirably employed is Raney Nickel although other reducing metalcatalysts such as platinum may be used to advantage in certain situations. Step 9 is especially applicable to production of compounds offormula lb in which the alkylamino substituent is dialkylamino,particularly, dimethylamino, although compounds lb having anN-alkylamino substituent may be also obtained when carrying out thereaction with the amount of aldehyde limited to about the stoichiometricamount for the reaction. The product compound Ib may be isolated fromthe reaction of Step9 by working up in a conventional manner.

Others methods may be employed for preparation of the compounds lb, andsuch procedure also includes those in which a compound I or lb is thestarting material. For example, compounds lb in which R is dialkylaminomay be prepared from a corresponding N-alkylamino derivative by reactionwith appropriate alkyl halide, as illustrated in Example 55. Certainmore specific compounds of formula lb may be also prepared by subjectinga compound I having a suitably activated chloro substituent to reactionwith an alkylamine in presence of a catalyst according to establishedprocedure.

It will be evident that in general the particularly preferred procedurefor preparation of a compound of formula I, and in particular those inwhich R is an alkylamino, will vary depending on one or more of severalknown factors including the particular compound desired, availability ofstarting materials and apparatus, costs and the like. In the usual case,the abovedescribed Steps 7, 8 and 9 are preferred for preparation ofcompounds lb in which the alkylamino substituent is N-alkylamino or tobe placed at the 6-position of the quinazolinone product. Steps 1 and 6are more suitable for preparation of compounds lb having a dialkylaminosubstituent and are usually preferred for preparation of compounds inwhich the alkylamino substituent is to be placed at other'than the6-position.

For the preparation of those compounds of formula I wherein R representsa branched alkyl substituent and the branching occurs on the carbon atomdirectly attached to the ring nitrogen atom, e.g., isopropyl andsec-butyl, it is most advantageous to employ the process of Step 1 orStep 6 since said processes afford better yields of the desired product.

Various of the quinazolines employed as starting materials in Step 3 areknown and can be prepared as described in the literature [see, e.g., J.Chem. Soc., 1927 (1952)]. Such others which are not specificallydisclosed may be prepared from available materials in analogous manneror by other known procedures.

Alternatively, the quinazolines (IV) may be prepared by oxidizing thecorresponding 3,4-dihydroquinazolines which in turn are prepared byreacting quinazoline (or substituted quinazoline) with either anarylmagnesium halide or an aryl lithium compound. These processes areillustrated below:

oxidation Step potassium permanganate N (M T l,

It [V wherein R, R" and n may be as defined above and X representschloro or bromo. It is, however, usually desirable to apply theoxidation Step 1 1 as well as the oxidation Step 4 previouslyillustrated to situations in which R is other than amino, alkylamino,alkylthio, hydroxy, mercapto, cyano and alkylamino. The reaction of thequinazoline with either the aryl-magnesium halide or aryl lithiumcompound is carried out in conventional manner and the quinazolines,aryl lithium compounds and Grignard reagents employed in the reactionare either known or can be readily prepared from available materials byestablished procedure known to those skilled in the art. Oxidation ofthe 3,4- dihydro-quinazoline is readily effected in an inert organicsolvent (dioxane) and at room temperature.

Similarly, various of the quinazolinones used as starting materials forthe preparation of the l-metallo derivatives (III) are known and can beprepared as described in the literature, for example, by reaction of theappropriately substituted 2-aminobenzophenone with urea at temperaturespreferably between 16020 C., followed by crystallization from a suitablesolvent, e.g., ethanol, as disclosed in Jap. Pat. 20865/65 published9/16/63, and illustrated in Examples 29, 31 and 35. Such others whichare not specifically disclosed may be prepared from available materialsin analogous manner. Such quinazolinones can be also prepared from theappropriately substituted 2- aminobenzophenones by the reaction of Step1, as illustrated in Example 17.

The o-aminobenzophenones which are compounds 11 and employed in Step 1are likewise either known or can be prepared from available materials byprocedures known in the art. In situations where R is 5- nitro-orS-trifluoromethyl in compounds 11, it is preferred to prepare suchcompounds by reaction of the corresponding 5-R (nitro ortrifluoromethyl)-2- chloro-benzophenone with an appropriate amine (R'NHin the presence of a suitable catalyst, such as a mixture of copper andcuprous chloride, as demonstrated in Examples 22 24, inclusive.

The o-aminobenzophenonimines of formula VII employed as startingmaterial in Step 6 also are know or can be prepared from availablematerials by one or more of a number of well-established procedures, aswill be evident to those skilled in the art. In general, the compoundsof formula VII may be produced by reaction of a correspondingo-aminobenzophenone of formula II with ammonia, desirably in a sealedreactor under anhydrous conditions and at elevated temperatures andpressures. Reaction temperatures are suitably in the range of 100 C. to200 C., preferably 110 C. to 150 C. A catalyst such as a Lewis acid,e.g., zinc chloride, may be employed to advantage in the process. Thereaction is preferably carried out with ammonia as solvent, or with asuitable co-solvent, e.g., dioxane, followed by recovery in aconventional manner. Another well-known procedure for producingcompounds VII involves the tosylation, alkylation and detosylation of anappropriately substituted anthranilonitrile to obtain the corresponding2-aminobenzonitrile which is then reacted with a phenyl Grignardcompound or phenyllithium compound, followed by working up in a knownmanner to obtain the compound of formula VII.

The o-aminobenzophenones of formula II and the oaminobenzophenoniminesof formula VII in which R is a branched alkyl substituent in which thebranching occurs on the carbon atom attached to the amino nitrogen,e.g., isopropyl, are in most situations conveniently and preferablyprepared by direct alkylation of a corresponding 2-amino startingmaterial with an alkyl halide as illustrated herein in Example 37.

Certain compounds of formula I, in particular, those in which R isnitrogen-containing, will form acid addition salts and thosepharmaeeutically acceptable salts not materially affecting thepharmacological properties of the compounds of formula I are alsoincluded within the scope of the invention. Such salts include the acidaddition salts, e.g., the hydrochloride, fumarate, formate, acetate,citrate, sulfonate, malonate, tartrate, methane sulfonate, salicylateand hydrosulfate. The acid addition salts may be produced as desiredfrom the corresponding free bases by conventional procedures.Conversely, the free bases may be obtained from the salts or byprocedures known in the art.

The compounds of structural formula I are useful because they possesspharmacological activity in animals. In particular, the compounds areuseful as anti-inflammatory agents as indicated by theCarrageenan-induced edema test on rats (oral administration). For suchuse, the compounds may be combined with a pharmaceutically acceptablecarrier, and such other conventional adjuvants as may be necessary, andadministered orally in such forms as tablets, capsules,

elixirs, suspensions and the like or parenterally in the form of aninjectable solution or suspension. The dosage administered will, ofcourse, vary depending upon the compounds used and the mode ofadministration. However, in general, satisfactory results are obtainedwhen administered at a daily dosage of from about .15 milligram to about100 milligrams per kilogram of body weight, preferably given in divideddoses 2 to 4 times a day, or in a sustained release form. For mostmammals the administration of from about milligrams to about 1000milligrams of the compound per day provides satisfactory results anddosage forms suitable for internal administration comprise from about 3milligrams to about 500 milligrams of the compound in admixture with asolid or liquid pharmaceutical carrier or diluent.

The compounds I of the invention are also useful as analgesics asindicated by application of pressure to yeast-inflamed foot of the rat(oral administration). They are also useful as anti-pyretics asindicated by inhibition of bacterial lipopolysaccharides-induced fever(oral administration). For such uses, the compound may be administeredto obtain satisfactory results at dosages and in modes similar to thoseemployed in the treatment of inflammation.

A representative formulation is a tablet prepared by conventionaltabletting techniques and containing the following ingredients:

Ingredient Parts by Weight l-lsopropyl-7-methyl-4-phenyl-2 50 (lH)-quinazolinone Tragacanth 2 Lactose 39.5 Corn Starch 5 Talcum 3Magnesium Stearate 0.5

From the standpoint of anti-inflammatory activity based on theabove-mentioned tests, the compounds I of general preference are thosein which R is methyl, ethyl, isopropyl, tertiary butyl, ally] andpropargyl, more preferably, ethyl, isopropyl and tertiary butyl, andespecially isopropyl, R" is preferably unsubstituted phenyl in mostsituations. The very good anti-inflammatory activity of compounds inwhich R is, for example, ethyl or isopropyl may be discernibly and evensharply increased in certain situations in which R is other thanhydrogen, the R substituents of interest in this connection usuallybeing methyl, ethyl, chloro or an alkylamino such as dialkylamino. Onemay specifically mention, for example, the unexpected and remarkableanti-inflammatory activity demonstrated by 7-methyll-isopropyl-4-phenyl-2( l H )-quinazolinone compared, for example, withthe already very good 6-methyl-l-isopropyl-4-phenyl-2(ll-l)-quinazolinone. As is often the casewith compounds exhibiting anti-inflammatory and analgesic activity,compounds 1 within the scope of the invention also exhibitanti-bradykinin activity as demonstrated on intravenous administrationto the guinea pig, foriexample, in doses of 4.0 to 5000 micrograms perkilogram of body weight. Thus, one might also mention the compoundl-isopropyl-4-phenyl-2(lH)-quinazolinone because of its unusually highanti-bradykinin activity and uses of interest based on such activitysuch as the treatment of atheroschlerosis as described by P. Shimarnotoet al., Asian Medical J. 8, 825 (1965) and P. Shimamoto et al., Am.Heart J. 71,216 (1966).

In addition, it has been found that compounds of formula l in which R isN-alkylamino or dialkylamino may be also used as hypotensive agents, asindicated by a lowering of blood pressure on intravenous administrationto the anesthetized dog (IO-20 mg./kg. dosage). For such use the dosagewill vary depending upon the compound used, mode of administration andthe like. However, in general, satisfactory results are obtained whenadministered at a daily dosage of from about i to 20 milligrams perkilogram of body weight. For most mammals, the administration of fromabout 50 to about 400 milligrams of the compound per day is satisfactoryand dosage forms suitable for internal administration comprise fromabout 12 to 200 milligrams in admixture with a solid or liquidpharmaceutical carrier or diluent. Modes and forms of administration aresimilar for those used in treatment of inflammation.

The following examples show representative compounds encompassed withinthe scope of this invention and the manner in which such compounds areprepared. However, it is to be understood that the examples are forpurposes of illustration only.

EXAMPLE 1 l -Methyl-4-phenyl-2( l H )-quinazolinone N 4/ E 0 i i 1'.

Step A. Preparation of l-methyl-4-phenyl-quinazolinium iodide A solutionof 2.0 g. of 4-phenylquinazoline in 10 ml. of methyl iodide is kept atroom temperature overnight and then refluxed for 8 hours. The resultingmixture is then cooled, and the crystalline material thus obtained isfiltered off and washed with diethyl ether to obtainlmethyl-4-phenyl-quinazolinium iodide, m.p. 20020l C.

Step B. Preparation of l-methyl-4-phenyl-2( ll-l)-quinazolinone.

To a suspension of 5.7 g. of 1-methyl-4-phenyl-quinazolinium iodide in300 ml. of purified dioxane is added slowly a solution of 4 g. ofpotassium permanganate in 150 ml. of water. The reaction mixture ismaintained at room temperature for 15 minutes and then 10 ml. ofcommercial dioxane and 25 ml. of 1% aqueous solution of sodiumthiosulfate are added to destroy the excess permanganate and reduce anyiodine which is formed. The resulting mixture is then filtered and thefiltrate concentrated to about 100 ml. in vacuo. To the resultant isadded ml. of methylene chloride and 80 ml. of water. The organic phaseis separated, washed first with 50 ml. of aqueous (2 percent) sodiumcarbonate solution and then with 40 ml. of water and then dried oversodium sulfate and evaporated in vacuo. The residue is dissolved in l0ml. of ethyl acetate. To the resulting solution is added 8 ml. ofdiethyl ether and the resulting crystalline material filtered off toobtain 1- mcthyl-4-phenyl-2( ll-l )-quinazolinone, m.p. l42-l 43 C.

EXAMPLE 2 l-Methyl-4-phenyl-2(1H) -quinazolinone (via Step 5) Step A.Preparation of 1-methyl-4-phenyl-l,2,3,4- tetrahydroquinazoline To asolution of 18 g. of 1-methyl-4-phenyl-quinazolinium iodide in 500 ml.of absolute ethanol and 250 ml. of methylene chloride is added, in smallportions and at room temperature, 6 g. of sodium borohydride. After 45minutes, 3 ml. of acetic acid is added to destroy the excess sodiumborohydride. The solvents are then evaporated off in vacuo, and theresidue treated with 180 ml. of methylene chloride and 10 ml. of aqueousN sodium hydroxide solution. The organic phase is then separated, washedwith 250 ml. of water, dried over sodium sulfate and then evaporated toobtain 1-methyl-4-phenyl-l,2,3,4-tetrahydroquinazoline as an oil. StepB. Preparation of 1-methy1-4-phenyl-2(lH)-quinazolinone To a solution of12 g. of 1-methyl-4-phenyl-1,2,3,4- tetrahydroquinazoline in 500 ml. ofpurified dioxane is slowly added a solution of 13.2 g. of potassiumpermanganate in 250 ml. of water. After the addition is completed thereaction mixture is kept at room temperature for minutes and then 25 ml.of commercial dioxane is added to destroy the excess permanganate. Theresulting mixture is then filtered, and the filtrate concentrated toabout 100 ml. in vacuo. To the resultant is added 120 ml. of methylenechloride and 150 ml. of water. The organic phase is separated, washedfirst with 150 ml. of aqueous (2 percent) sodium carbonate solution,then with 100 ml. of water and then dried over sodium sulfate andevaporated in vacuo. The residue is dissolved in 30 ml. of ethylacetate. To the resulting solution is added 15 ml. of diethyl ether, andthe crystalline material thus obtained filtered off to obtain l-methyl-4-phenyl-2(lH)-quinazolinone, m.p. 142143C. 1

EXAMPLE 3 EXAMPLE 4 1Ethyl-4-phenyl-2( 1 H)-quinazolinone (via Step 2)To a solution of 2.2 g. of 4-pheny1-2(1H)-quinazolinone in 50 ml. ofdimethylacetamide is added, at room temperature, 0.75 g. of sodiumhydride (50 percent in mineral oil). The resulting mixture is stirredfor 15 minutes at room temperature and then 4 ml. of ethyl iodide isadded. The mixture is stirred for an additional 30 minutes at roomtemperature and then heated at 60 C. for 30 minutes to complete thereaction. The mixture is then evaporated in vacuo to remove most of thesolvent, and the residue poured over g. of ice. The resulting solidmaterial is filtered off, dissolved in 50 ml. of methylene chloride andthe resulting solution dried over sodium sulfate and the solvent thenevaporated in vacuo. The resulting oily residue is crystallized fromethyl acetate to obtain l-ethyl-4- phenyl-2( lH)-quinazolinone, m.p.183l85C.

EXAMPLE 5 6-Chloro-l-methyl-4-phenyl-2( 1H )-quinazolinone N we. l l

To a solution of 2.56 g. of 6-chloro-4-phenyl-2(1H)- quinazolinone in100 ml. of dimethylformamide is added, at room temperature, 0.75 g. ofsodium hydride (50 percent in mineral oil). The resulting mixture isstirred for 15 minutes at room temperature, and then 4 ml. of methyliodide is added. The mixture is then stirred at room temperature for anadditional 30 minutes, then evaporated in vacuo to remove most of thesolvent and then poured over 100 g. of ice. The resulting solid materialis filtered off, dissolved in 50 ml. of methylene chloride and theresulting solution dried over sodium sulfate and the solvent thenevaporated in vacuo. The resulting oily residue is crystallized fromethyl acetate to obtain 6-chloro-1- methyl-4-phenyl-2(1H)-quinazolinone,m.p. 223224 C.

EXAMPLE 6 1-Methyl-4-(p-chlorophenyl)-2( 1H)-quinazolinone (III-Ir Nportions and at room temperature, 3.5 g. of sodium borohydride. After 45minutes l.5 ml. of acetic acid is added to destroy the excess sodiumborohydride. The solvents are then evaporated off in vacuo and theresidue treated with 100 ml. of methylene chloride and ml. of aqueous 5Nsodium hydroxide solution. The organic phase is then separated, washedwith 250 ml. of .water, dried over sodium sulfate and then evaporated toobtain l-methyl-4-(p-chlorophenyn-l ,2,3,4- tetrahydroquinazoline as anoil.

Step C. Preparation of l-methyl-4-(p-chlorophenyl)-2 l H)-quinazolinoneTo a solution of 0.5 g. ofl-methyl-4-(p-chlorophenyl)-1,2,3,4-tetrahydroquinazoline in 20 ml. ofpurified dioxane is slowly added a solution of 0.625 g. of potassiumpermanganate in 12 ml. of water. After the addition is completed, thereaction mixture is kept at room temperature for minutes and then S m].of commercial dioxane is added to destroy the excess permanganate. Theresulting mixture is then filtered, and the filtrate concentrated toabout 10 ml. in vacuo. The resulting product is poured over ice-water,the resulting mixture filtered and the residue washed with water toobtain l-methyl-4-(p-chlorophenyl)-2( l H )quinazolinone, m.p. 195 C.

The 4-(p-chlorophenyl)-quinazoline employed in Step A is prepared in thefollowing manner:

An ethereal solution of p-chlorophenyl lithium is prepared by reacting0.96 g. of p-bromochlorobenzene in 10 ml. of absolute diethyl ether with3.1 ml. of a 1.6 molar solution of n-butyl lithium in hexane, at roomtemperature for 30 minutes. To this solution is added a solution of 0.65g. of quinazoline in [0 ml. of absolute diethyl ether and the resultingmixture stirred for 10 minutes. The resulting lithium salt is decomposedby shaking the reaction mixture with ID ml. of water. The organic phaseis then separated, dried over anhydrous sodium sulfate, filtered and thefiltrate evaporated in vacuo. The residue is crystallized from ethylacetate to obtain 4-(p-chlorophenyl)3,4- dihydroquinazoline, m.p. l66- l67 C. i To a solution of 5.0 g. of 4-(p-chlorophenyl)-3,4-dihydroquinazoline in 200 ml. of dry dioxane is added, portionwise atroom temperature, 60 ml. of aqueous potassium permanganate solution(5.27 g. of potassium permanganate in 100 ml. of water). The excesspermanganate is then destroyed by the dropwise addition of formic aciduntil the solution is colorless. The precipitated inorganic material isthen filtered off and the filtrate evaporated in vacuo. The residue istreated with 100 ml. ofa 1:1 mixture of methylene chloride and water,the organic phase separated, dried over anhydrous sodium sulfate,filtered and the filtrate evaporated in vacuo. The residue iscrystallized from diethyl ether to obtain 4-(p-chlorophenyl)quinazoline, m.p. l22l23 C.

EXAMPLE 7 Following the procedure of Step A of Example 6 and employingan equivalent amount of the quinazolines enumerated below in place ofthe 4-(p-chlorophenyl)- quinazoline used therein there are obtained theproducts set forth below:

Following the procedure of Step B of Example 6 and employing, in order,an equivalent amount of the products enumerated above in place of thel-methyl-4- (p-chlorophenyl)-quinazolinium iodide used in Step B ofExample 6 there are obtained the tetrahydroquinazolines set forth below:

1. l-methyl-4-(p-methoxyphenyl)-1,2,3 ,4-

tetrahydroquinazoline (oil).

l-methyl-4-(2,6-dimethoxyphenyl)-l,2,3,4- tetrahydroquinazoline, m.p.157 C. (after crystallization from ethyl acetate). 3.l-methyl-4-(m-chlorophenyl)-l,2,3,4-

tetrahydroquinazoline (oil). 4.l-methyl-4-(m-trifluoromethylphenyl)-l,2,3,4-

tetrahydroquinazoline (oil). 5. l-methyl-4-(2,3-dimethylphenyl)-l,2,3,4-

tetrahydroquinazoline (oil). Following the procedure of Step C ofExample 6 and employing, in order, an equivalent amount of thetetrahydroquinazolines enumerated above in place of thel-methyl-4-(p-chlorophenyl)-l ,2,3,4-

tetrahydroquinazoline used in Step C of Example 6 there are obtained thequinazolinones set forth below:

1. l-methyl-4-(p-methoxyphenyl)-2( 1H )-quinazolinone, m.p. 184 C.(after recrystallization from ethyl acetate).

l-methyl-4-(2,6-dimethoxyphenyl)-2( ll-l )-quinazolinone, m.p. l66-l67C. (after recrystallization from ethyl acetate).

- 3. l-methyl-4-(m-chlorophenyl)-2( lH)-quinazolinone, m.p. 96 C. (afterpurification by precipitation of the hydrochloride salt from acetone andsubsequent liberation of the free base and crystallization thereof fromdiethyl etherpetroleum ether l :l

4. l-methyl-4-(m-trifluoromethylphenyl)-2(1H)- quinazolinone, m.p.l65l67 C. (after recrystallization from ethyl acetate-diethyl ether (l:l

5. l-methyl -4-(2,3-dimethylphenyl)-2(lH)-quinazolinone, m.p. l86-l88 C.(after recrystallization from ethyl acetate).

EXAMPLE 8 Following the procedure of Example 5 and employing anequivalent amount of 4-phenyl-2(lH)-quin- EXAMPLE ll azolinone in placeof 6-chloro-4-phenyl-2(ll-l)-quinazolinone and the halide reactantenumerated below in lJSPl-opyI'4'phenyl'n l H)'qumazolmone place ofmethyl iodide there are obtained the products CH1 CH1 set forth below:(|3H N Halide Reactant Product =0 (l) n-propyl iodidel-n-propyl-4-phenyl-2(1H)- quinazolinone, m.p. l3lC. N 2 n-butyl bromidel-n-butyl-4-phenyl-2( n1 quinazolinone, m.p. l03-l04 l C. (aftercrystallization from ethyl acetate-diethyl ether (3) n-amyl bromidel-n-amyl-4-phenyl-2(lH)- quinazolinone, m.p. l2l-l22 C. 4 allyl iodidel-allyl-4-phenyl-2(lH)- I A mlxlflre of 21 of Crude guinaz emn 59l60isopropylammobenzophenone, 40 g. of urethane and (5) propargy] iodide lprpargyl 4 pheny 2( my 1.5 g. of zinc chloride is heated for 4 hours atl80-200 quinazolinone, m.p. 181C. C. (oil bath). The resulting mixtureis cooled to room (elm "Yslamzamn fwm temperature and then there isadded thereto 200 ml. of ethanol).

methylene chlonde The resultmg m1xture 1s filtered EXAMPLE 9 and thefiltrate extracted twice with 100 ml. (each) of water. The organic phaseis dried over anhydrous sodi-'chlom'l'methy]'4'(0'chlrophenyl)'2(lH)'quin' um sulfate and evaporatedin vacuo. The residue is azolmone crystallized from ethyl acetate toobtain l-isopropyl-4- 3 25 phenyl-2(lH)-quinazolinone,m.p. 140C. l f c oEXAMPLE 12 1: l-lsobutyl-4-phenyl-2(1H)-quinazolinone (31 CH; CH,

1 m Cl +112 N b=0 35 III Following the procedure of Example 5 andemploying an equivalent amount of6'-chloro-4-(o-chloropheny])-2(1H)-quinazolinone, dimethylacetamide andsodium methoxide in place of 6-chloro-4-phenyl-2(1H)- quinazolinone,dimethylformamide and sodium hydride, respectively, there is obtained6-chloro-l- A mixture of 21 g. of crudeo-isobumethyl-4-(o-chlorophenyl)-2( lH)-quinazolinone, m.p.tylaminobenzophenone, 40 g. of urethane and L5 g. of l9l-l94 C. zincchloride is heated for 4 hours at l80200 C. (oil bath). The resultingmixture is cooled to room tem- EXAMPLE 10 perature and then there isadded thereto 200 ml. of 1 Methy| 4 (p hydmxypheny|)2(lvflyquinazolinone methylene chloride. The resulting mixture isfiltered and the filtrate extracted twice with 100 ml. (each) of CH;water. The organic phase is dried over anhydrous sodii; um sulfate andevaporated in vacuo. The residue is 0:0 crystallized from ethylacetate-diethyl ether (1:1) to l obtainl-isobutyl-4-phenyl-2(lH)-quinazolinone, m.p. l20l22C.

EXAMPLE 13 l-Methallyl-4-phenyl-2(lH)-quinazolinone CH, CH:

A mixture of 3 g. of 4-(p-methoxyphenyl)-l-methyl- 1 2( 1H)-quinazolinone and 20 ml. of 48 percent aqueous hydrobromic acid isrefluxed for 20 hours, concen- (1 trated in vacuo and then made alkaline(pH 9) with 2N N aqueous ammonium hydroxide solution. The basic mixtureis then extracted three times with 30 ml. (each) of ethyl acetate. Thecombined ethyl acetate extracts are then dried over anhydrous sodiumsulfate and then i evaporated in vacuo and the residue crystallized fromethyl acetate to obtain l-methyl-4-p-hydroxyphenyl)-2 T a r d ol i (40 Cf 6 7 f 4 h (lH)-quinazolinone, m.p. 29l-293C. 2( lH)-quinazolinone inl50 ml. of dry dimethylacetamide is added 2.25 g. of sodium hydride (50percent in mineral oil). The resulting mixture is stirred for 30 minutesat 3540 C. and then 6 ml. of methallyl chloride is added. The resultingmixture is stirred for 3 hours at 80l00 C. and then 300 ml. of ice wateris added. The resulting mixture is extracted twice with 200 ml. (each)of ethyl acetate. The combined ethyl acetate extracts are dried overanhydrous sodium sulfate, filtered and evaporated in vacuo. The residueis 'crystallized from 50 ml. of ethyl acetate to obtain 1-isopropylaminobenzophenone, 20 g. of urethane and l g. of zinc chlorideis heated for'2 hours at 180-200 C. (oil bath). The resulting mixture iscooled to room temperature and then there is added thereto 200 ml. ofmethylene chloride. The resulting mixture is filtered and the filtrateextracted twice with l ml. (each of water. The organic phase is driedover anhydrous sodium sulfate and evaporated in vacuo. The residue iscrystallized from acetone and dried for 48 hours at 45 C. in high vacuumto obtain 6-chloro-l-isopropyl-4- phenyl-2(1l-l)-quinazolinone.m.p.149-150 c.

v EXAMPLE 15 6-Chloro-4-(o-chlorophenyl)-1 -isopropyl-2( 1H)-quinazolinone A mixture of 8.2 g. of crude 2', 5-dichloro-2-isopropylaminobenzophenone, 17 g. of urethane and 1.5 g. of zincchloride is heated for 4 hours at 1809-200 C. (oilbath). The resultingmixture is cooled to room temperature and then there is added thereto200 ml. of methylene chloride. The resulting mixture is filtered and thefiltrate extracted twice with 100 ml. (each) of water. The organic phaseis dried over anhydrous sodium sulfate and evaporated in vacuo. Theresidue is crystallized from diethyl ether-petroleum ether (1:1) toobtain 6-chloro-4-(o-chlorophenyl)-l-isopropyl- 2(1H)-quinazolin0ne,m.p. 147149 C.

EXAMPLE 16 6-Chlorol -ethyl-4-phenyl-2( 1H )-quinazolinone N a... I 1.

To a hot solution of 5.2 g. of 6-chloro-4-phenyl-2 (1H)-quinazolinone in200 ml. of dimethylformamide is added 1.5 g. of sodium hydride (50percent in mineral oil). The resulting mixture is stirred for 15 minutesat room temperature and then 10 ml. of ethyl idodide is added. Theresulting mixture is stirred for 20 hours at 60 C., then evaporated invacuo to remove most of the solvent and the residue poured over g. ofice. The resulting solid material is filtered off, dissolved in 50 ml.of methylene chloride and the resulting solution dried over anhydroussodium sulfate and the solvent then evaporated in vacuo. The residue iscrystallized from ethyl acetate to obtain 6-chloro-lethyl-4-phenyl-2(lH)-quinazolinone, m.p. 163 C.

EXAMPLE 17 6,7-dimethyl-l-ethyl-4-phenyl-2( 1H)-quinazolinone N mo r =011.0 N

Step A: Preparation of 6,7-dimethyl-4-phenyl-2(1H)- quinazolinone Amixture of 10 g of 4,5-dimethyl-2- aminobenzophenone, 20 g of urethaneand 2 g of zinc chloride is heated for two hours at C to 200 C(oilbath). The resulting mixture is cooled to room temperature and theresulting solid material treated with 100 ml of 1:1 mixture of methylenechloride and water. The organic phase is separated, dried over anhydroussodium sulphate, filtered and the solvent is evaporated. The residue iscrystallized from ethyl acetate to obtain beige crystals of6,7-dimethyl-4-pheny1-2( lH)-quinazolinone having a mp greater than 280C. Step B: Preparation of 6,7-dimethyl-1-ethyl-4-phenyl- 2( lH)-quinazolinone To a solution of 4.5 g. of 4,5-dimethyl-2-aminobezophenone in 100 ml. of diethylacetamide is added, at roomtemperature, 1.0 g. of sodium hydride (50 percent in mineral oil). Theresulting mixture is stirred for 15 minutes at room temperature and then10 ml. of ethyl iodide is added. The procedure of Example 4 is followedto complete preparation with crystallization from ethanol/diethyl ether(1:1) to obtain 6,7- dimethyl-l-ethyl-4-phenyl-2(lH)-quinazolinone, m.p.176 C. to 180 C.

EXAMPLE 1s 6,7-Dimethyl-l-isopropyl-4-phenyl-2(1H)-quinazolinone HsC CH:([1 N H3O N HC Step A: Preparation of 4,5-dimethyl-2-isopropylaminobenzophenone A mixture of 9.5 g. of 4,5-dimethyl-2-aminobenzophenone, g. of sodium carbonate and 30 ml. of isopropyl iodideis refluxed for hours, poured onto 200 ml. ice water, and extractedthree times each with 100 ml. of ethyl acetate. The organic phase isseparated, dried over anhydrous sodium sulphate, filtered, and thefiltrate evaporated to dryness in vacuo to obtain 10 g. of reactionmixture as a crude oil. The oil is purified by column chromatographyusing silica gel with benzene as eluant to obtain a pure yellow oil of4,5-dimethyll2-isopropylaminobenzophenone. Step B: Preparation of6,7-dimethyl-1-isopropyl-4- phenyl-2( 1H )-quinazolinone Applyingequivalent amounts and following the procedure of Example 11, the driedresidue is crystallized from diethyl ether to obtain yellow prisms of6,7- dimethyll -isopropyl-4-phenyl-2( 1H )-quinazolinone; m.p.135C.137C.

EXAMPLE 19 4-Phenyl-l ,6,7-trimethyl-2( 1H )-quinazolinone To a solutionof 4.5 g. of 6,7-dimethyl-4-phenyl-2 (1H) quinazolinone (prepared byStep A of Example 17) in 100 ml. of dimethylformamide is added, at roomtemperature, 0.75 g. of sodium hydride (50 percent) in mineral oil). Theresulting mixture is stirred for 15 minutes at room temperature, andthen 4 ml. of methyl iodide is added. The mixture is stirred at roomtemperature for an additional 30 minutes, then evaporated in vacuo toremove most of the solvent and then poured over 100 g. of ice. Theresulting solid material is filtered off, dissolved in 50 ml. of methylchloride and the resulting solution dried over sodium sulphate and thesolvent then evaporated in vacuo. The resulting residue is crystallizedfrom diethyl ether to obtain white crystals or4-phenyl-1,6,7-trimethyl-2-(1H)-quinazolinone, m.p. 204-206 C.

EXAMPLE 20 l-isopropyl-4-(p-tolyl )-2( l H )-quinazolinone Step A:Preparation of 2-isopropylamino-4'-methylbenzophenone A mixture of 9.5 gof 2-amino-4-methylbenzophenone, 10 g of sodium carbonate and 30 ml ofisopropyl iodide is refluxed for five days, poured onto 200 ml icewater, and extracted three times with ml ethyl acetate. The organicphase is separated, dried over anhydrous sodium sulphate, filtered andevaporated to dryness in vacuo to obtain 10 g of reaction mixture as acrude oil which is purified by column chromatography using silica gelwith benzene as eluant to obtain a pure yellow oil of2isopropylamino-4'- methyl-benzophenone. Step B: Preparation ofl-isopropyl-4-(p-tolyl)-2(1H)- quinazolinone A mixture of 21 g. of2isopropylamino-4-methylbenzophenone 40 g. of urethane and 1.5 g. ofzinc chloride is heated for 4 hours at 180200 C. (oil bath). Theresulting mixture is cooled to room temperature and there is addedthereto 200 ml. of methylene chloride. Completing the procedure as inExample 11, there is crystallized from dimethyl ether yellow prisms ofthe 1-isopropyl-4-(p-tolyl)-2(1H)- quinazolinone, m.p. 138 C. to 140C.

EXAMPLE 21 6,7-Dimethyl-4-phenyl-l-propargyl-2(1H)-quinazolinone $HFCECHN on. 1:0 CH; N

equivalent EXAMPLE 22 1-Ethyl-4phenyl-6-trifluoromethyl-2( l H)-quinazolinone ethylaminobenzophenone A mixture of g. ofS-trifluoromethyl-Z- chlorobenzophenone, 500 mg. of powdered copper, 500ml. of cuprous chloride and 100 ml. liquid ethylamine is heated in asealed steel cylinder for 2 hours at 130 C.140 C. The reaction mixtureis taken up in 200 ml. of ethyl acetate, extracted twice with water. Theorganic phase is separated, dried over anhydrous sodium sulphate,filtered and evaporated to dryness in vacuo. The resulting residue isheated in ml. of dioxane and ml. of6 N hydrochloric acid. The resultingsolution is made alkaline with sodium hydroxide and is extracted twicewith 100 ml. of ethyl acetate. The organic phases are combined, driedover anhydrous sodium sulphate and evaporated to dryness in vacuo. Thethus-obtained residue is crystallized from ethanol to yield yellowprisms of 5-trifluoromethyl-2- ethylaminobenzophenone; m.p. 78 C. 80 C.Step B: Preparation of trifluoromethyl-2( lH)-quinazolinone Proceedingas in Example 3, above, a mixture of an amount of S-trifluoromethyl-Z-ethylaminobenzophenone, 2 g. of urethane and 20 mg. of zinc chloride isheated for 20 hours at temperatures of 140 C.l5.0 'C. (oil bath).Completing the procedure as in Example 3, the residue is crystallizedfrom diethyl ether to give yellow prisms of the l-ethyl-4-phenyl-6-trifluorom ethyl-2( 1 H )-quinazolinone, which sublimes at180 C.

EXAMPLE 23 l-Ethyl-6-nitro-4-phenyl-2( lH)-quinazolinone 5-nitro-2-l-ethyl-4-phenyl 6- Step B: Preparation ofl-ethyl-6-nitro-4-phenyl-2(1H)- quinazolinone Proceeding as in Example11, above, an equivalent amount of 5-nitro-2-ethylaminobenzophenone, 40g. of urethane and 1.5 g. of zinc chloride is heated for 4 hours at180-200 C. (oil bath). Completing the procedure as in Example ll, theresidue from the organic phase is crystallized from methanol to giveyellow prisms of the l-ethyl-6-nitro-4-phenyl-2( lH)-quinazolinone, m.p.2142l5 C.

EXAMPLE 24 6-Nitro- 1 -isopropyl-4-phenyl-2( 1H )-quinazolinone CH: lCH; \l= N02 \l/ Step A: Preparation of 5-nitro-2-isopropylaminobenzophenone A mixture of 15 g. of5-nitro-2-chlorobenzophenone, 700 mg. of powdered copper, 700 mg. ofcuprous chloride, 15 ml. of ethanol, and 15 ml. of liquid isopropylamineis refluxed for 20 hours. Completing the procedure as in Example 23(Step A), above, the residue is crystallized from ethanol to give yellowprisms of 5-nitro-2-isopropylaminobenzophenone; m.p. 155C. Step B:Preparation of 6-nitro-1-isopropyl-4-phenyl- 2( lH)-quinazolinoneFollowing the procedure of Example 23 (Step B), above, and employingequivalent amounts, the residue of the organic phase is crystallizedfrom ethyl acetate to give yellow prisms of6-nitro-l-isopropyl-4-phenyl- 2(1H)-quinazolinone; m.p. l90l92C.

EXAMPLE 25 6-Amino-l -isopropyl-4-phenyl-2( 1H )-quinazolinone Asolution of 12.0 g of 6-nitro-l-isopropyl-4-phenyl- 2(l'H)-quinazolinonedissolved in 240 ml of hot ethanol is heated to boiling and withstirring there is added ml of water, and then 16 g of iron filings.There is then also added dropwise with stirring a solution made up of 80ml ethanol, 20 ml water and 4 ml 2N hydrochloric acid over the course of40 minutes. The resulting mixture is refluxed for 3 hours, and there isthen added to the hot solution 4 ml of 2N sodium hydroxide followed byfiltering and concentration in vacuo to remove most of the ethanol.There is added to the concentrate 100 ml of ethyl acetate followed byextraction of the organic phase 3 times each with 50 ml of dilutehydrochloric acid. The aqueous phases are combined and made alkalinewith sodium hydroxide followed by 2 extractions each with 100 ml ofmethylene chloride. The organic phases are combined and dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to dryness.The residue is crystallized from ethyl acetate to obtain yellow prismsof 6-amin0-lisopropyl-4-phenyl-2( lH)-quinazolinone; mp 2l0 215 C.

EXAMPLE 26 6-acetamidol -isopropyl-4-phenyl-2( 1H )-quinazolinone CHs TCH: 1 T" NII CHaCO EXAMPLE 27 6-Bromol -isopropyl-4-phenyl-2( 1H)-quinazolinone CH1 I OH: 0

Br N

A mixture of 4.2 g of 6-amino-l-isopropyl-4-phenyl- 2(1H)-quinazolinoneprepared as in Example 25, above, and dilute hydrobromic acid isdiazotized at a temperature of 05 C with ml 1N sodium nitrite. Theresulting diazonium salt solution is then added dropwise to 300 ml of ahot solution of cuprous bromide prepared in the well-known manner forSandmeyer-type reactions. The reaction mixture is then heated for 10minutes at 100 C to form a precipitate which is filtered off and addedto 100 ml of methylene chloride and 50 ml of 2N sodium hydroxide. Theorganic phase is dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to dryness. The residue is purified by columnchromatography applying aluminum oxide and methylene chloride as eluant,and then crystallized from ethyl acetate to obtain crystalline prisms of6-bromo-l-isopropyl-4-phenyl-2(1H)- quinazolinone; mp l42l43 C.

EXAMPLE 28 6-Cyano-l-isopropyl-4-phenyl-2(1H)-quinazolinone A mixture of4.2 g. of 6-amino-l-isopropyl-4-phenyl- 2(1H)-quinazolinone prepared asin Example 25, above, and dilute hydrochloric acid is diazotized at atemperature of 0-5 C. with 15 ml. 1N sodium nitrite. The resultingsolution is promptly added (within 5 minutes) to a solution of 12 g. ofsodium cyanide and 22 g. of cuprous cyanide in 500 ml. of water at roomtemperature, followed by heating for 45 minutes to a temperature of l00C. (water bath). The resulting mixture is cooled to room temperature andthere is added thereto 200 ml. of chloroform, and the insoluble materialfiltered out. The organic phase is separated and extracted once with ml.of l N hydrochloric acid and once with 50 m]. dilute sodium bicarbonatesolution. The organic phase is then dried over anhydrous sodiumsulphate, filtered and evaporated in vacuo to dryness. The crudereaction product is then purified as a solution in methylene chloride byfiltration through a short column containing alumina. The filtrate issubjected to crystallization employing ethanol/diethyl ether (lzl) toobtain crystalline prisms of 6-cyano-1 -isopropyl-4-phenyl-2( l H)-quinazolinone, m.p. l25C.-l28C.

EXAMPLE 29 l-Ethyl-6-methyl-4-phenyl-2(1H)-quinazol inone Step A:Preparation of 6-methyl-4-phenyl-2( lH)-quinazolinone A mixture of 5 g.of 5-methyl-2-aminobenzophenone and 4 g. of urea is heated at atemperature of 200 C. for 2 hours. The solid residue is treated with 100ml.

of 50 percent aqueous solution of ethanol and filtered to obtain thecrystalline reaction product at beige crystals of6-methyl-4-phenyl-2(1H)-quinazolinone, m.p. 280281C. Step B: Preparationof 1-ethyl-6-methyl-4-phenyl- 2( lH)-quinazolinone Proceeding as inExample 4, above, and employing equivalent amounts with6-methyl-4-phenyl-2(1H)- quinazolinone replacing the 4-phenyl-2(lH)-quinazolinone of Example 4, there is obtained on crystallization ofthe residue with diethyl ether yellow needles ofl-ethyl-6-methy]-4-phenyl-2(1H)-quinazolinone, m.p. 180C.

EXAMPLE 30 C I OH; N

Step A: Preparation of isopropylaminobenzophenone Proceeding as inExample 18 (Step A) and using equivalent amounts,-methyl-2-aminobenzophenone in admixture with sodium carbonate andisopropyl iodide is refluxed for 4 days. Completing the procedure as inExample 18 (Step A), there isobtained a pure yellow oil of5-methyl-2-isopropylaminobenzophenone. Step B: Preparation ofl-isopropyl-6-methyl-4-phenyl- 2( 1H )-quinazolinone Proceeding as inExample 3, above, and employing equivalent amounts with 5-methyl-2-isopropylaminobenzophenone replacing the omethylaminobenzophenone ofExample 3, the residue of the organic phase is crystallized fromethanol/diethyl ether (1:2) to obtain white prisms of 1-isopropyl-6-methyl-4-phenyl-2(1I-l)-quinazolinone, m.p. l701 71 C.

5-methyl-2- EXAMPLE 31 l-Ethyl-7-chloro-4 phenyl-2( 1H)-quinazolinoneStep A: Preparation of 7-chloro-4-phenyl-2(1H)-quinazolinone Proceedingas in Example 29.(Step A), above, and employing equivalent amounts,4-chl0ro-2- aminobenzophenone is reacted to obtain on filtration of theethanol solution crystals of 7-chloro-4-phenyl-2 (lH)-quinazolinone,m.p. 275277 C. Step B: Preparation of l-ethyl-7-chloro-4-phenyl- 2( 1H)-quinazolinone Proceeding as in Example 16, above, and employingequivalent amounts with 7-chloro-4-phenyl-2(1H)- quinazolinone replacingthe 6-chloro-4-phenyl-2(1H)- quinazolinone of Example 16, the residue iscrystallized from ethyl acetate to obtain l-ethyl-7-chloro-4-phenyl-2(lH)-quinazolinone,m.p. 187188C.

EXAMPLE 32 1-allyl-7-chloro-4-phenyl-2( 1H )-quinazolinone CH:CH=CH27-Chloro-4-phenyl-2( 1 H )-quinazolinone prepared as in Example 29 (StepA), is reacted according to the procedure of Example 16 employingequivalent amounts to obtain on crystallization from ethyl acetate1-allyl-7-chloro-4-phenyl-2( 1H )-quinazolinone, m.p. 173C 174C.

EXAMPLE 33 7-Chloro-1-isopropyl-4-phenyl-2(1H )-quinazolinone CH3 /CHa E01 /N =0 Step A: Preparation of 4-chloro-2- isopropylaminobenzophenoneEmploying equivalent amounts and proceeding as in Example 18 (Step A),above, except that reflux is conducted over a period of four days,4-chloro-2- aminobenzophenone is reacted to obtain from the columnchromatography a purified yellow oil 4-chloro-2-isopropylaminobenzophenone. Step B: Preparation of7-chloro-l-isopropyl-4-phenyl- 2(1H)-quinazolinone Employing equivalentamounts and proceeding as in Example 1 1, above, 4-chloro-2-isopropylaminobenzophenone is reacted in place of theo-isopropylaminobenzophenone of Example 1 l, and the residue of theorganic phase is crystallized from ethyl acetate to obtain7-chloro-1-isopropyl4-phenyl- 2(1H)-quinazolirione, m.p. -l68 C.

EXAMPLE 34 6,7-'Dimethoxy-l -isopropyl-4-phenyl-2( 1H )-quinazolinone/CHa 5 IL CH2 CHaO =0 omo N Step A: Preparationisopropylaminobenzophenone Employing equivalent amounts 4,5-dimethoxy-2-aminobenzophenone is reacted according to the procedure of Example 18(step A) except that the reflux is conducted for a period of 2 1% days.The product obtained from the column chromatography is a purified yellowoil of 4,5-dimethoxy-2- isopropylaminobenzophenone. Step B: Preparationof 6,7-dimethoxy-1-isopropyl-4- phenyl-2( 1H )-quinazolinone Employingequivalent amounts and proceeding as in Example 1 1, above,4,5-dimethoxy-2- isopropylaminobenzophenone is reacted in place of theo-isopropylaminobenzophenone of Example 11, and the dried organic phaseis purified by column chromatography employing alumina. The residue iscrystallized from acetone/petroleum ether (1:1) to obtain white prismsof 6,7-dimethoxy-l-isopropyl-4-phenyl- 2(1H)-quinazolinone, m.p. 148-l50C.

of 4,5-dimethoxy-2- EXAMPLE 35 6-Methylthiol -ethyl-4-phenyl-2( l H)-quinazolinone CHaS Step A: Preparation of 6-methylthio-4-phenyl-2(1H)-quinazolinone Proceeding as in Example 29 (Step A),S-methylmercapto-2-aminobenzophenone is reacted with urea in equivalentamounts to obtain 6-methylthio-4-phenyl- 2( l l-l)-quinazolinone, mp 219to 221 C. Step B: Preparation of 6-methylthio-1ethyl-4-phenyl-2(1H)-quinozol inone Proceeding as in Example 4, above, and employingequivalent amounts, 6-methylthio-4-phenyl-2(1H)- quinazolinone isreacted in place of the 4-phenyl-2(1 H)-quinazolinone of Example 4, andthe residue is crystallized from ethyl acetate to obtain6-methylthioisopropylaminobenzophenone Proceeding as in Example 18 (StepA), above, methylthio-2-aminobenzophenone is reacted to obtain afterpurification a yellow oil of 5-methylthio-2- isopropylaminobenzophenone.Step B: Preparation of 1-isopropyl-6-methylthio-4-phenyl-2(lH)-quinazolinone Proceeding as in Example 11, above, andemploying equivalent amounts with 5-methylthio-2-isopropylaminobenzophenone replacing the oisopropylaminobenzophenone ofExample 11, there is obtained on crystallization from diethyl etherpetroleum ether (1 :1) crystals of l-isopropyl-6-methyl-thio-4-phenyl-2( 1H )-quinazolinone, m .p. 9395 C.

EXAMPLE 37 1-lsopropyl-7-methyl-4-phenyl-2( 1H )-quinazolinone CE: /CHa(3H N H3O \C=O Step A: Preparation of 4-methyl-2-isopropylaminobenzophenone A mixture of 7 g. of 4-methyl-2-aminobenzophenone, 6.35 g. of sodium carbonate and 18.8 ml. of2-iodopropane is stirred and refluxed for 3 days. The cooled reactionmixture is then diluted with 200 ml. of benzene and washed twice withwater and twice with brine. The organic phase is separated, dried overanhydrous sodium sulfate and concentrated in vacuo to removesubstantially all of the benzene. The resulting yellow oil is dissolvedin about 10 ml. of methylene chloride and subjected to columnchromatography employing alumina (about 400 g.) and methylene chlorideas eluant to give a first fraction which on concentration in vacuo toremove methylene chloride produced a yellow oil of 4-methyl-2-isopropylaminobenzophenone. Step B: Preparation of1-isopropyl-7-methyl-4-phenyl- 2(1H)-quinazolinone A mixture of 5.9 g.of 4-methyl-2- isopropylaminobenzophenone prepared in Step A above, 13.9g. of urethane and 500 milligrams of zinc chloride is heated at atemperature of 190 C. for 1% hours. There is then additionally added 7g. of urethane and 250 milligrams of zinc chloride, and the heatingcontinued at a temperature of 190 C. for an additional 2-5; hours. Theresulting mixture is cooled to about C. and diluted with chloroform. Theresulting mixture is then filtered and the filtrate washed first withwater and then with brine. The organic phase is separated, dried overanhydrous sodium sulfate and concentrated in vacuo to removesubstantially all of the chloroform and obtain an oily residue which isdissolved in a small amount of about 20 ml. of methylene chloride. Theresulting solution is then diluted with about 40 ml. of ethyl acetateand concentrated in vacuo to crystallize l-isopropyl-7-methyl-4-phenyl-2( lH)-quinazolinone; m.p. 137 to 138 C.

ybenzophenone, 15 g. of anhydrous potassium carbonate and 40 ml. of2-iodopropane is refluxed for 4 days. The cooled reaction mixture isthen diluted with 200 ml. of benzene and washed twice with water andtwice with brine. The organic phase is separated, dried over anhydroussodium sulfate and concentrated in vacuo to remove substantially all ofthe benzene. The resulting oil is dissolved in about 10 ml. of methylenechloride and subjected to column chromatography employing alumina (about400 g.) and methylene chloride as eluant to give a first fraction whichon concentration in vacuo to remove methylene chloride produced an oilof 4-methoxy-2-isopropylaminobenzophenone. Step B: Preparation ofl-isopropyl-7-methoxy-4-phenyl-2( lH)-quinazolinone A mixture of 5.9 g.of 4-methoxy-2- isopropylaminobenzophenone, prepared in Step A above, 20g. of urethane and 1.2 g. of zinc chloride is heated at a temperature of2002l5 C. for 40 minutes. There is then additionally added about l g. ofurethane and 600 mg. of zinc chloride and the heating is continued at atemperature of 200- -2l5 C. for about an additional l hour. Theresulting mixture is cooled to about 100 C. and diluted with chloroform.The resulting mixture is then filtered and the filtrate washed firstwith water and then with brine. The organic phase is separated, driedover anhydrous sodium sulfate and concentrated in vacuo to removesubstantially all of the chloroform and obtain an oily residue which isdissolved in a small amount of about 10 ml. of methylene chloride. Theresulting solution is then diluted with about 40 ml. of ethyl acetateand concentrated in vacuo to crystallize l-isopropyl-7-meth oxy-4-phenyl- 2( lH)-quinazolinone; m.p. l33l 37 C.

EXAMPLE 39 7-Hydroxyl -isopropyl-4-phenyl-2( l H )-quinazolinone CHa NE=O A mixture of 1.0 g. of l-isopropyl-7-methoxy-4-phenyl-2(1H)-quinazolinone prepared as in Example 38 and 5 ml. of 48percent hydrobromic acid is refluxed for 20 hours. The resulting mixtureis diluted with ml. water, made alkaline (pH 10) with 2N sodiumhydroxide, and extracted twice each with 50 ml. ethyl acetate to removenon-acidic products. The aqueous phase is separated, treated with 2Nhydrochloric acid to produce a precipitate which is recovered byfiltration. The solid is recrystallized from ethanol to obtain7-hydroxyl -isopropyl-4-phenyl-2( l H )-quinazolinone, m.p. 266267 C.

EXAMPLE 40 l-Ethyl-6-mercapto-4-phenyl-2( l H )-quinazolinone l zHs /N Amixture of 3.0 g. of 6-methylthio-l-ethyl-4-phenyl- 2(ll-l)-quinazolinone prepared as in Example 35 and 25 ml. of 48 percenthydrobromic acid is refluxed for 4 days. The resulting mixture isneutralized with 2N sodium hydroxide and then extracted twice each with100 ml. of ethyl acetate. The organic phases are combined, dried overanhydrous sodium sulfate, filtered, and evaporated in vacuo. Theresulting residue is crystallized from ethyl acetate to obtainl-ethyl-6-mercapto-4 -phenyl-2( l l-l)-quinazolinone, m.p. 200204 C.

EXAMPLE 41 6,8-Dimethyll -isopropyl-4-phenyl-2( l H )-quinazolinone CH3CHa $113 (3H N CH3 Step A: Preparation of 3,5-dimethyl-2-isopropylaminobenzophenone A mixture of 14.6 g. of2-amino-3,5.-dimethylbenzophenone (prepared by reactions known fromSternbach et al., J. Org. Chem. 27, 3781 (1962)), 15g. of anhydrouspotassium carbonate and 36 ml. of 2- iodopropane is refluxed for 4 daysand then heated for 24 hours in a sealed vessel at a temperature of C.The cooled reaction mixture is then diluted with 200 ml. of benzene andwashed twice with water and twice with brine. The organic phase isseparated, dried over anhydrous sodium sulfate and concentrated in vacuoto remove substantially all of the benzene. The resulting oil isdissolved in about l0 ml. of methylene chloride and subjected to columnchromatography employing alumina (about 400 g.) and methylene chlorideas eluant to give a first fraction which on concentrationin vacuo toremove methylene chloride produced an oil of3,5-dimethyl-2isopropylaminobenzophenone. Step B: Preparation of6,8-dimethyl-l-isopropyl-4- phenyl-2( ll-l )-quinazolinone A mixture of1 g of 3,5-dimethyl-2- isopropylaminobenzophenone, prepared in Step Aabove, 4 g of urethane and 50 mg of zinc chloride is heated at atemperature of 190 200 C for 45 minutes. There is then additionallyadded about 2 g of urethane and 25 mg of zinc chloride and the heatingis continued at a temperature of 190 200 C for about an additional 1hour. The resulting mixture is cooled to about 100 C and diluted withchloroform. The resulting mixture is then filtered and the filtratewashed first with water and then with brine. The organic phase isseparated, dried over anhydrous sodium sulfate and concentrated in vacuoto remove substantially all of the chloroform and obtain an oily residuewhich is dissolved in a small amount of about 10 ml of methylenechloride. The resulting solution is then diluted with about 40 ml ofethyl acetate and concentrated in vacuo to crystallize6,8-dimethy1-1-isopropyl-4-phenyl- 2(1H)-quinazolinone; mp 168- 169C.

EXAMPLE 42 5,7-Dimethyl-l-isopropyl-4-phenyl-2(1H)-quinazolinone CH3 CH2(7H N OHa \C:()

s: (11H: i

Step A: Preparation of 4,6-dimethyl-2- isopropylaminobenzophenone Amixture of g. of 2-amino-4,6-dimethylbenzophenone (prepared by reactionsknown from E. Ritchie, .1. Proc. Roy. Soc. N.S. Wales 80, 33 (1946) andChem. Abstracts 41, 3094(c) (1947)), 5 g. of anhydrous potassiumcarbonate and 20 ml. of 2- iodopropane is refluxed for 30 hours. Thecooled reaction mixture is then diluted with 200 ml. of benzene andwashed twice with water and twice with brine. The organic phase isseparated, dried over anhydrous sodium sulfate and concentrated in vacuoto remove substantially all of the benzene. The resulting oil isdissolved in about ml. of methylene chloride. The resulting solution isdiluted with pentane and concentrated in vacuo to crystallize4,6-dimethyl-2- isopropylaminobenzophenone; m.p. 8788 C. Step B:Preparation of 5,7-dimethyl-1-isopropyl-4- phenyl-2(1H)-quinazolinone Amixture of 6.1 g of 4,6-dimethyl-2- isopropylaminobenzophenone, preparedin Step A above, g of urethane and 1 g of zinc chloride is heated at atemperature of 200 210 C for one hour. There is then additionally addedabout 8 g of urethane and 500 mg of zinc chloride and the heating iscontinued at a temperature of 200 210 C for about an additional onehour. The resulting mixture is cooled to about 100 C and diluted withchloroform. The resulting mixture is then filtered and the filtratewashed first with water and then with brine. The organic phase isseparated, dried over anhydrous sodium sulfate and concentrated in vacuoto remove substantially all of the chloroform and obtain an oily residuewhich is dissolved in a small amount of about 10 ml of methylenechloride. The resulting solution is then diluted with about 40 ml ofethyl acetate and concentrated in vacuo to crystallize5,7-dimethy1-1-isopropyl-4-phenyl-2 (1H)-quinazo1inone; mp 145- 147 C.

EXAMPLE 43 7-Chloro-1-isopropyl-6-methyl-4-phenyl-2(1H)-quinazolinoneStep A: Preparation of 2-amino-4-chloro-5-methylbenzophenone To 142 g.of benzoyl chloride is added a total of 57 g. of3-chloro-4-methylaniline in small portions over a period of 1% hour attemperature of 1 10 C. The resulting mixture is heated to a temperatureof 180 C. and 140 g. of zinc chloride added in divided portions over 1hour and heating then continued at temperature of 225230 C. for 1 1%hours. The resulting mixture is cooled to temperature of 120130 C. andthere is added a mixture of 150 ml. of acetic acid, 100 ml. of water and150 ml. of concentrated sulfuric acid. The resulting mixture is thenrefluxed for 3 hours, poured onto 2 liters of ice and water andextracted 3 times each with 300 ml of methylene chloride. The organiclayers are combined, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The resulting oily residue is distributed betweena liquid system composed of 500 ml. of 2N sodium hydroxide and 300 ml.of methylene chloride and the organic phase washed with water, then withbrine, dried, filtered and evaporated in vacuo to obtain a crudematerial which is purified by crystallization from diethyl ether/pentane(1:2) to obtain 2-amino-4-chloro-5- methylenebenzophenone, m.p. 96 C.Step B: Preparation of 4-chloro-2-isopropylamin0-5- methylbenzophenone Amixture of 22 g. of 2-amino-4-chloro-5-methylbenzophenone obtained fromStep A, above, 20 g. of sodium carbonate and 60 ml. of 2-iodopropane isrefluxed for 120 hours. The cooled reaction mixture is then diluted with300 ml. of methylene chloride and extracted twice each with ml. ofwater. The organic phase is separated, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to remove solvent. Theresulting oil is dissolved in a small amount of methylene chloride andsubjected to column chromatography employing alumina and methylenechloride as eluant to give a first fraction which on concentration invacuo to remove methylene chloride produced an orange oil of4-chloro-2-isopropylamino-5 methylbenzophenone. Step C: Preparation of7-chloro-1-isopropyl-6-methyl- 4-phenyl-2(1H)-quinazolinone Proceedingas in Step B of Example 37, above, and employing equivalent amounts with4-chloro-2- isopropylamino-S-methylbenzophenone replacing the4-methyl-2-isopropylaminobenzophenone of Example. and subjected tocolumn chromatography employing 37, there is obtained on crystallizationfrom methylene alumina (about 50 g) and methylene chloride as eluantchloride/diethyl ether (about 1:10) crystals of 7- to give a firstfraction which on concentration in vacuochloro-l-isopropyl-6-methyl-4-phenyl-2(lH)-quinto remove methylenechloride produced an oil of 2- azolinone, m.p. 190l91 C. 5isopropylamino-o-methylbenzophenone.

Step B: Preparation of l-isopropyl-5-methyl-4-phenyl- EXAMPLE 44 2(lH)-quinazolinone 7-Chloro-l-ethyl-6-methyl-4-phenyl-2(1H)quin- Amixture of 1 g of p py y amunone benzophenone, prepared in Step A above,4 g of 02m 10 urethane and 200 mg of anhydrous zinc chloride is N heatedat a temperature of 200 210 C for 30 Cl minutes. There is thenadditionally added about 2 g of ll2r urethane and l00 mg of zincchloride and the heating is CH1 l 5 continued at a temperature of 200210 C for about 1 an additional one hour. The resulting mixture iscooled to about 100 C and diluted with chloroform. The resulting mixtureis then filtered and the filtrate washed first with water and then withbrine. The organic phase is separated, dried over anhydrous sodiumsulfate and concentrated in vacuo to remove substantially all of thechloroform and obtain an oily residue which is dissolved in a smallamount of about 10 ml of methylene chloride and subjected to columnchromatography employing alumina (about g) and methylene chloride aseluant. The first fraction is then diluted with about ml of ethylacetate and concentrated in vacuo to Step A: Preparation of7-chloro-6-methyl4-phenyl- 2( 1H )-quinazolinone A mixture of 10 g. of2-amino-4-chloro-5-methylbenzophenone prepared as in Step A of Example43 and 10 g. of urea is heated at a temperature of about l80-200 C. for3 '22 hours. The solid residue is crystallized fromdimethylsulfamide/water (1:1) to obtain crystals of7-chloro-6-methyl-4-phenyl-2(lH)-quinazolinone, m.p. 3103 15 C.

, azolinone; mp 153- 154 C. Step B: Preparation of7-chloro-l-ethyl-6-methyl-4- 3O phenyl-2( ll-l)-quinazolinone A P 4 To asolution of 7 g. of 7-chloro-6-methyl-4-phenyl- 2(ll-l)-quinazolinone in200 ml. of dimethylsulfamide EmP'Wmg the of 1 A and B Q Examis added, atroom temperature, 1.4 g. of sodium hydride P and the ppropnatecorrcspondmg start percent in mineral oil). The resulting mixture is 5 lmatenals approxlmately equwalent amountsrone stirred for 30 minutes atroom temperature and then 20 is able to Obtam the compomds of Formula ISet forth ml. of ethyl iodide is added and the mixture is stirred below:for 20 hours at room temperature. The mixture is then P PY P Y l'n'qpoured on 1 liter of ice water to obtain a precipitate azolmonei 11 2L1(crystanlzatlon from which is filtered off, dried and recrystallizedfrom 40 ethyl g methylene chloride/ether (1:5 to obtain 7-chloro-l- P P'P y '2 l'n'q ethyl 6 methyl 4 phenyl 2(1H) quinaZonOne; azolinone, m.p.l6' 7 l 68 C. (crystallization from 185.11 0 methylene chloride/diethylether).

C. l-Isopropyl-7-methylthio-4-phenyl-2( 1H )-quin- EXAMPLE 45 45azolinone, m.p. l35-137 C. (crystallization from ethylacetate/pentane(1:1)). l-lsopropyl-5-methyl 4-phenyl 2(1l-l) quinazolinone D- 6 Ethy1 1isopropyl 4 phenyl z( lH) quin azolinone, m.p. 1161 17 C.(crystallization from (1311 ethyl acetate/diethyl ether (1:5)). E.l-lsopropyl-7-methyl-4-(p-tolyl)-2( 1H )-quinazolinone, m.p. l56-l57 C.(crystallization from N ethyl acetate). I I F.llsopropyl7-methyl-4(p-methyoxyphenyl 1H:

2( ll-l)-quinazolinone, m.p. l63165 C. (crystallization from ethylacetate).

G. 1-lsopropyl-6-meth0xy-4-phenyl-2(1H)-quinazolinone, m.p. 140143 C.(Crystallization from methylene chloride/diethyl ether (1:2)). Step A:Preparation of 2-isopropylamino-6-methyl- EXAMPLE 47 A mixture of 1.4 gof 2-am1no-6-methylbenzophenone, 2g of anhydrous potassium carbonateEmploying the reactions of Steps A and B of Examand 20 ml of2-iodopropane is refluxed for hours. ple 17, above, and the appropriatecorresponding start- The cooled reaction mixture is then diluted with200 ml ing materials in approximately equivalent amounts, one of benzeneand washed twice with water and twice with is also able to obtain thecompounds of Formula I set brine. The organic phase is separated, driedover anforth below: hydrous sodium sulfate and concentrated in vacuo toA. l-Ethyl-7-methyl-4-phenyl-2(1H)-quinazolinone, remove substantiallyall of the benzene. The resulting m.p. l60162 C. (crystallization fromethyl oil is dissolved in about 10 ml of methylene chloride acetate).

crystallize l-isopropyl-5-methyl-4-phenyl-2( 1H )-quinnitrobenzophenone,20 ml. of ethanol and 30 ml. of tert. butylamine is added 1.5 g. ofcopper powder and 1.5 g. of cuprous chloride. The resulting mixture isrefluxed for 5 days with stirring, the crystallized productprecipitated, filtered and washed with ethanol to obtain yellow crystalsof 5-nitro-2-tert. butylaminobenzophenone, m.p. 157158 C. Step B:Preparation of S-nitro-Z-tert. butylaminobenzophenonimine A mixture of 2g. of S-nitro-tert. bu-

tylaminobenzophenone, 15 ml. of anhydrous ammonia- (low condensed airmoisture content), and 20 mg. zinc chloride is heated in a sealedstainless steel cylinder at temperature of ll-l20 C. for 3 days. Excessammonia is evaporated from the resulting mixture and the residuerecrystallized from ethanol to obtain yellow crystals of 5-nitro-2-tert.butylaminobenzophenonimine, m.p. 146 C. Step C: Preparation of l-tert.butyl'6-nitro-4-phenyl-2 (1H )-quinazolinone To a solution of 1.3 g. of5-nitro-2-tert. butylaminobenzophenonimine, and 5 ml. of triethylaminein 30 ml. of benzene is added 25 ml. of a 12 percent solution ofphosgene in benzene at temperature between 5 C. to 20 C. The resultingsolution is allowed to stand at room temperature for 15 minutes and isthen evaporated in vacuo to dryness. The residue is distributed by aliquid system composed of 50 ml. of 0.5 N sodium carbonate and 50 ml. ofmethylene chloride, followed by an additional extract of the aqueousphase with 30 ml. of methylene chloride. The combined methylene chloridesolutions are dried over anhydrous sodium sulfate, evaporated in vacuoto dryness and the residue crystallized from ethyl acetate to obtainlight yellow needles of l-tert. butyl-6-nitro-4-phenyl-2(lH)-quinaz0linone, m.p. 206 C.

EXAMPLE 49 l-isopropyl-7-methyl-6-nitro-4-phenyl-2( l H )-quinazolinoneTo a cooled solution (0.5 C.) of 13.9 g. of 1-isopropyl-7-methyl-4-phenyl-2( lH)-quinazolinone (prepared as in Example37) in 50 ml. of concentrated sulfuric acid is added dropwise over l0minutes a solution of 6.07 g. of potassium nitrate in 15 ml. ofconcentrated sulfuric acid. The resulting solution is allowed to warm toroom temperature and then stirred for 2 hours. The solution is thenpoured into ice water and the resulting solid is isolated by filtration.The solid is dissolved in ml. of diethyl ether and the solution iswashed once with 100 ml. of water before being dried over anhydroussodium sulfate. The mixture is filtered and the filtrate is evaporatedin vacuo to yield a residue which is crystallized from 50 ml. of ethylacetate to obtain l-isopropyl-7-methyl-6-nitro-4-phenyl-2(1H)-quinazolinone, m.p. l92194 C.

EXAMPLE 50 6-Dimethylaminol -isopropyl-7-methyl-4-phenyl-2(lH)-quinazolinone A mixture of 8 g. of l-isopropyl-7-methyl-6-nitro-4-phenyl-2(ll-l)-quinazolinone (prepared as in Example 49) and 8 g. ofRaney Nickel in 200 ml. of methenol, 100 ml. of dioxane and 20 ml. of a37 percent solution of formaldehyde in methenol is shaken under hydrogenat room temperature and at an initial pressure of 50 lb/sq. in. Themixture is shaken for a total of 3 hours by which time uptake ofhydrogen has ceased. The catalyst is then removed by filtration and thefiltrate is concentrated in vacuo. The residue is crystallized from 50ml. of ethyl acetate to yield6-dimethylamino-lisopropyl-7-methyl-4-phenyl-2( l H )-quinazolinone,m.p. l84l86C.

EXAMPLE 5l 6-Dimethylamino-l -isopropyl-4-phenyl-2( l H )-quinazolinoneEmploying equivalent amounts, 6-nitro1-isopropyl-4-phenyl-2(ll-l)-quinazolinone (prepared as in Example 24) is subjectedto reaction following the procedure of Example 50, and the residue ofthe organic phase is crystallized from ethyl acetate to obtain 6-dimethylamino-l-isopropyl-4-phenyl-2(1H)-quinazolinone, m.p. 167-168C.

EXAMPLE 52 6-N-ethylamino- 1 -isopropyl-4-phenyl-2( 1H )-quinazolinone.

A mixture of 2 g. of 6-amino-l-isopropyl-4-phenyl- 2(1l-l)-quinazolinoneand 5 g. of Raney Nickel W2 in 100 ml. of ethanol is stirred and heatedunder reflux for 2 hours. The hot mixture is then filtered throughdiatomaceous earth obtained under the trademark Celite" and the filtrateconcentrated in vacuo. The residue so obtained is crystallized fromdiethyl ether to yield 6-N-ethylamino- 1 -isopropyl-4-phenyl-2( 1Hquinazolinone, m.p. 224 C.

EXAMPLE 53 A o-N-isopropylamino-1-isopropyl-4-phenyl-2(1H)-quin-.azolinone.

A mixture of 1 g. of 6-amino 1-isopropyl-4-phenyl- 2(1l-l)-quinazolinoneand 1 g. of anhydrous sodium carbonate in 10 ml. of isopropyl iodide isstirred and heated under reflux for 4 hours. The resulting mixture isthen cooled, diluted with 100 ml. of diethyl ether, filtered and thefiltrate is concentrated in vacuo to yield a residue which iscrystallized from a mixture of diethyl ether/methylene chloride (5:1) toobtain 6-N- isopropylamino-l-isopropyl-4-phenyl-2( ll-l)-quinazolinone,m.p. 222 C.

The reaction of Example 4 is repeated except that the reaction isallowed to continue for about 48 hours and the reaction mixture issubjected to conventional hydrogen chloride treatment to obtain oncrystallization from acetone/diethyl ether (1:1) crystals of 6-diisopropylamino-1-isopropyl-4-phenyl-2( 1H )-quinazolinonehydrochloride, m.p. 225 C. (decomposition).

EXAMPLE 54 7-Dimethylamino-1-isopropyl-4-phenyl-2(1H)-quinazolinone.

CH: Ha

CH OH; I

C=O CHa Step A: Preparation of 4-dimethylamino-2- nitrobenzonitrile.

A mixture of 89 g. of 4-chloro-3-nitro-N,N- dimethylaniline and 48 g. ofcuprous cyanide in 450 ml. of dimethylacetamide is stirred and heatedunder reflux for 6 hours. To complete the reaction, a further 24 g. ofcuprous cyanide is then added and the mixture is refluxed for 3 hours.The resulting solution is cooled and added slowly to 5 l. of ice water.A solid precipitate is obtained which is isolated by filtration anddried. A mixture of the precipitate in 2 l. of methylene chloride and200 ml. of methanol is stirred and heated under reflux for 1 hour andthen cooled and filtered through Celite." The filtrate is concentratedin vacuo and the residue is crystallized from ml. of ethanol to yield4-dimethylamino-2-nitrobenzonitrile, m.p. 182C.

Step B: Preparation of 4-dimethylamino-2- aminobenzonitrile.

To a refluxing mixture of 30 g. of 4-dimethylamino- 2-nitrobenzonitrilein 600 ml. of ethanol, 60 ml. of dioxane and 80 ml. of concentratedhydrochloric acid is added in portions 30 g. of iron powder. When theaddition is complete the mixture is refluxed for 1 hour. it is'thenfiltered hot through Celite and the filtrate is concentrated in vacuo toone quarter of its volume. The residue is poured into 500 ml. oficewater to which 2N sodium hydroxide solution is then added until it isbasic. The aqueous mixture is extracted twice with 200 ml. of methylenechloride. The organic phase is dried over anhydrous sodium sulfate andconcentrated in vacuo to give a residue which is crystallized from 1ethanol to obtain 4-dimethylamino-2- aminobenzonitrile, m.p. C. Step C:Preparation of 4-dimethylamino-2-

2. A compound of claim 1 wherein R'' represents allyl, methallyl orpropargyl and R and R'''' are as defined in claim
 1. 3. The compound ofclaim 1 which is 1-methyl-4-phenyl-2(1H)-quinazolinone.
 4. The compoundof claim 1 which is 1-ethyl-4-phenyl-2(1H)-quinazolinone.
 5. Thecompound of claim 1 which is6-chloro-1-methyl-4-phenyl-2(1H)-quinazolinone.
 6. The compound of claim1 which is 1-methyl-4-(m-chlorophenyl)-2(1H)-quinazolinone.
 7. Thecompound of claim 1 which is 1-propyl-4-phenyl-2(1H)-quinazolinone. 8.The compound of claim 1 which is 1-butyl-4-phenyl-2(1H)-quinazolinone.9. The compound of claim 1 which is 1-amyl-4-phenyl-2(1H)-quinazolinone.10. The compound of claim 1 which is1-allyl-4-phenyl-2(1H)-quinazolinone.
 11. The compound of claim 1 whichis 1-propargyl-4-phenyl-2(1H)-quinazolinone.
 12. The compound of claim 1which is 1-isopropyl-4-phenyl-2(1H)-quinazolinone.
 13. The compound ofclaim 1 which is 1-isobutyl-4-phenyl-2(1H)-quinazolinone.
 14. Thecompound of claim 1 which is6-chloro-1-isopropyl-4-phenyl-2(1H)-quinazoLinone.
 15. The compound ofclaim 1 which is 6-chloro-1-ethyl-4-phenyl-2(1H)-quinazolinone.
 16. Acompound of claim 1 wherein R represents hydrogen, halo, lower alkyl orlower alkoxy, and n, R'' and R'''' are as defined in claim
 1. 17. Acompound of claim 16 in which R is hydrogen or halo, and n is
 1. 18. Thecompound of claim 1 which is6,7-dimethyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone.
 19. The compoundof claim 1 which is 1-ethyl-6-nitro-4-phenyl-2(1H)-quinazolinone. 20.The compound of claim 1 which is1-isopropyl-6-nitro-4-phenyl-2(1H)-quinazolinone.
 21. The compound ofclaim 1 which is 6-amino-1-isopropyl-4-phenyl-2(1H)-quinazolinone. 22.The compound of claim 1 which is6-bromo-1-isopropyl-4-phenyl-2(1H)-quinazolinone.
 23. The compound ofclaim 1 which is 1-ethyl-6-methyl-4-phenyl-2(1H)-quinazolinone.
 24. Thecompound of claim 1 which is1-isopropyl-6-methyl-4-phenyl-2(1H)-quinazolinone.
 25. The compound ofclaim 1 which is 7-chloro-1-ethyl-4-phenyl-2(1H)-quinazolinone.
 26. Thecompound of claim 1 which is7-chloro-1-isopropyl-4-phenyl-2(1H)-quinazolinone.
 27. A compound ofclaim 1 in which R'''' is phenyl.
 28. A compound of claim 1 wherein R''represents methyl, ethyl or isopropyl, and n, R and R'''' are as definedin claim
 1. 29. A compound of claim 28 in which R'''' is phenyl.
 30. Acompound of claim 28 wherein R'' is isopropyl.
 31. A compound of claim30 in which R'''' is phenyl.
 32. A compound of claim 30 wherein R is7-methyl.
 33. The compound of claim 32 which is1-isopropyl-7-methyl-4-phenyl-2(1H)-quinazolinone.
 34. The compound ofclaim 32 which is 5,7-dimethyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone.35. The compound of claim 1 which is1-isopropyl-7-methoxy-4-phenyl-2(1H)-quinazolinone.
 36. The compound ofclaim 1 which is7-chloro-1-isopropyl-6-methyl-4-phenyl-2(1H)-quinazolinone.
 37. Thecompound of claim 1 which is1-isopropyl-5-methyl-4-phenyl-2(1H)-quinazolinone.
 38. The compound ofclaim 1 which is 7-ethyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone. 39.The compound of claim 1 which is6-ethyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone.
 40. The compound ofclaim 1 which is 1-isopropyl-7-methyl-4-(p-tolyl)-2(1H)-quinazolinone.41. The compound of claim 1 which is1-isopropyl-7-methyl-4-(p-methoxyphenyl)-2(1H)-quinazolinone.
 42. Thecompound of claim 1 which is1-ethyl-7-methyl-4-phenyl-2(1H)-quinazolinone.
 43. The compound of claim1 which is 1-ethyl-7-nitro-4-phenyl-2(1H)-quinazolinone.
 44. Thecompound of claim 1 which is1-methyl-7-methyl-4-phenyl-2(1H)-quinazolinone.
 45. A compound of claim1 in which R'' is tertiary butyl.
 46. A compound of claim 45 in whichR'''' is phenyl.
 47. The compound of claim 46 which is1-tert.-butyl-6-nitro-4-phenyl-2(1H)-quinazolinone.
 48. A compound ofclaim 1 in which R is selected from the group of hydrogen, halo, loweralkyl, lower alkoxy, hydroxy, nitro, amino, acetoamido, mercapto, cyano,trifluoromethyl and lower alkylthio, and R'', R'''' and n are as definedin claim
 1. 49. A compound of claim 1 in which R'' is isopropyl.
 50. Acompound of claim 1 in which R is N-alkylamiNo or dialkylamino.
 51. Acompound of claim 50 in which R'' is lower alkyl.
 52. A compound ofclaim 50 in which R is N-alkylamino.
 53. A compound of claim 50 in whichR is dialkylamino.
 54. A compound of claim 52 in which R'' is isopropyl.55. A compound of claim 54 in which R is N-alkylamino.
 56. A compound ofclaim 54 in which R is dialkylamino.
 57. A compound of claim 55 in whichthe other R is 7-alkyl of one to three carbon atoms.
 58. A compound ofclaim 56 in which the other R is 7-alkyl of one to three carbon atoms.59. A compound of claim 58 which is6-dimethylamino-1-isopropyl-7-methyl-4-phenyl-2(1H)-quinazolinone, or anacid addition salt thereof.
 60. A compound of claim 58 which is6-dimethylamino-1-isopropyl-4-phenyl-2(1H)-quinazolinone, or an acidaddition salt thereof.
 61. A compound of claim 57 which is6-N-ethylamino-1-isopropyl-4-phenyl-2(1H)-quinazolinone, or an acidaddition salt thereof.
 62. A compound of claim 57 which is6-N-isopropylamino-1-iso-propyl-4-phenyl-2(1H)-quinazolinone, or an acidaddition salt thereof.
 63. A compound of claim 56 which is7-dimethylamino-1-isopropyl-4-phenyl-2(1H)-quinazolinone, or an acidaddition salt thereof.
 64. A compound of the formula:
 65. A process forpreparing a compound of claim 1 wherein R'' represents methyl, R is fromthe group of hydrogen, halo, lower alkyl, lower alkoxy, nitro, acetamidoor trifluoromethyl, and n and R'''' are as defined in claim 1 with nsubject to the limitation recited in claim 1 when n is 2, whichcomprises treating a quinazoline of the formula
 66. A process of claim65 wherein the methyl halide is methyl iodide.
 67. A process forpreparing a compound of claim 1 wherein R'' represents methyl, R is fromthe group of hydrogen, halo, lower alkyl, lower alkoxy, nitro, acetamidoor trifluoromethyl, and n and R'''' are as defined in claim 1 with nsubject to the limitation recited in claim 1 when n is 2, whichcomprises treating a quinazoline of the formula
 68. The process of claim67 in which R is hydrogen, halo, lower alkyl or lower alkoxy.
 69. Aprocess of claim 67 wherein the methyl halide is methyl iodide.
 70. Aprocess for preparing a compound of claim 1 wherein R'' is methyl and nis 1 and R and R'''' are as defined in claim 54 which comprisesoxidizing the corresponding 1-methyl-1,2,3,4-tetrahydroquinazoline withsodium permanganate or potassium permanganate.